document_title: Hemoglobin

question_text: where is oxygen attached on a hemoglobin molecule

question_tokens: where is oxygen attached on a hemoglobin molecule

root

text: Hemoglobin

text: Research history[edit]

text: In 1825 J. F. Engelhard discovered that the ratio of iron to protein is identical in the hemoglobins of several species.[15] From the known atomic mass of iron he calculated the molecular mass of hemoglobin to n × 16000 (n = number of iron atoms per hemoglobin, now known to be 4), the first determination of a protein's molecular mass. This "hasty conclusion" drew a lot of ridicule at the time from scientists who could not believe that any molecule could be that big. Gilbert Smithson Adair confirmed Engelhard's results in 1925 by measuring the osmotic pressure of hemoglobin solutions.[16]

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text: The oxygen-carrying property of hemoglobin was discovered by Hünefeld in 1840.[17] In 1851,[18] German physiologist Otto Funke published a series of articles in which he described growing hemoglobin crystals by successively diluting red blood cells with a solvent such as pure water, alcohol or ether, followed by slow evaporation of the solvent from the resulting protein solution.[19] Hemoglobin's reversible oxygenation was described a few years later by Felix Hoppe-Seyler.[20]

text: In 1959, Max Perutz determined the molecular structure of hemoglobin by X-ray crystallography.[21][22] This work resulted in his sharing with John Kendrew the 1962 Nobel Prize in Chemistry for their studies of the structures of globular proteins.

text:
The role of hemoglobin in the blood was elucidated by French physiologist Claude Bernard.
The name hemoglobin is derived from the words heme and globin, reflecting the fact that each subunit of hemoglobin is a globular protein with an embedded heme group. Each heme group contains one iron atom, that can bind one oxygen molecule through ion-induced dipole forces. The most common type of hemoglobin in mammals contains four such subunits.

text: Genetics[edit]

text: Hemoglobin consists of protein subunits (the "globin" molecules), and these proteins, in turn, are folded chains of a large number of different amino acids called polypeptides. The amino acid sequence of any polypeptide created by a cell is in turn determined by the stretches of DNA called genes. In all proteins, it is the amino acid sequence that determines the protein's chemical properties and function.

text: There is more than one hemoglobin gene: in humans, hemoglobin A (the main form of hemoglobin present) is coded for by the genes, HBA1, HBA2, and HBB.[23] The amino acid sequences of the globin proteins in hemoglobins usually differ between species. These differences grow with evolutionary distance between species. For example, the most common hemoglobin sequences in humans and chimpanzees are nearly identical, differing by only one amino acid in both the alpha and the beta globin protein chains.[24] These differences grow larger between less closely related species.

text: Even within a species, different variants of hemoglobin always exist, although one sequence is usually a "most common" one in each species. Mutations in the genes for the hemoglobin protein in a species result in hemoglobin variants.[25][26] Many of these mutant forms of hemoglobin cause no disease. Some of these mutant forms of hemoglobin, however, cause a group of hereditary diseases termed the hemoglobinopathies. The best known hemoglobinopathy is sickle-cell disease, which was the first human disease whose mechanism was understood at the molecular level. A (mostly) separate set of diseases called thalassemias involves underproduction of normal and sometimes abnormal hemoglobins, through problems and mutations in globin gene regulation. All these diseases produce anemia.[27]

text: Variations in hemoglobin amino acid sequences, as with other proteins, may be adaptive. For example, hemoglobin has been found to adapt in different ways to high altitudes. Organisms living at high elevations experience lower partial pressures of oxygen compared to those at sea level. This presents a challenge to the organisms that inhabit such environments because hemoglobin, which normally binds oxygen at high partial pressures of oxygen, must be able to bind oxygen when it is present at a lower pressure. Different organisms have adapted to such a challenge. For example, recent studies have suggested genetic variants in deer mice that help explain how deer mice that live in the mountains are able to survive in the thin air that accompanies high altitudes. A researcher from the University of Nebraska-Lincoln found mutations in four different genes that can account for differences between deer mice that live in lowland prairies versus the mountains. After examining wild mice captured from both highlands and lowlands, it was found that: the genes of the two breeds are "virtually identical—except for those that govern the oxygen-carrying capacity of their hemoglobin". "The genetic difference enables highland mice to make more efficient use of their oxygen", since less is available at higher altitudes, such as those in the mountains.[28] Mammoth hemoglobin featured mutations that allowed for oxygen delivery at lower temperatures, thus enabling mammoths to migrate to higher latitudes during the Pleistocene.[29] This was also found in hummingbirds that inhabit the Andes. Hummingbirds already expend a lot of energy and thus have high oxygen demands and yet Andean hummingbirds have been found to thrive in high altitudes. Non-synonymous mutations in the hemoglobin gene of multiple species living at high elevations (Oreotrochilus, A. castelnaudii, C. violifer, P. gigas, and A. viridicuada) have caused the protein to have less of an affinity for inositol hexaphosphate (IHP), a molecule found in birds that has a similar role as 2,3-BPG in humans; this results in the ability to bind oxygen in lower partial pressures.[30]

text: Birds' unique circulatory lungs also promote efficient use of oxygen at low partial pressures of O2. These two adaptations reinforce each other and account for birds' remarkable high-altitude performance.

text: Hemoglobin adaptation extends to humans, as well. Studies have found that a small number of native Tibetan women have a genotype which codes for hemoglobin to be more highly saturated with oxygen.[31] Natural selection seems to be the main force working on this gene because the mortality rate of offspring is significantly lower for women with higher hemoglobin-oxygen affinity when compared to the mortality rate of offspring from women with low hemoglobin-oxygen affinity. While the exact genotype and mechanism by which this occurs is not yet clear, selection is acting on these women's ability to bind oxygen in low partial pressures, which overall allows them to better sustain crucial metabolic processes.

text: Synthesis[edit]

text: Hemoglobin (Hb) is synthesized in a complex series of steps. The heme part is synthesized in a series of steps in the mitochondria and the cytosol of immature red blood cells, while the globin protein parts are synthesized by ribosomes in the cytosol.[32] Production of Hb continues in the cell throughout its early development from the proerythroblast to the reticulocyte in the bone marrow. At this point, the nucleus is lost in mammalian red blood cells, but not in birds and many other species. Even after the loss of the nucleus in mammals, residual ribosomal RNA allows further synthesis of Hb until the reticulocyte loses its RNA soon after entering the vasculature (this hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and name).[33]

text: Structure[edit]

text: Hemoglobin has a quaternary structure characteristic of many multi-subunit globular proteins.[34] Most of the amino acids in hemoglobin form alpha helices, and these helices are connected by short non-helical segments. Hydrogen bonds stabilize the helical sections inside this protein, causing attractions within the molecule, which then causes each polypeptide chain to fold into a specific shape.[35] Hemoglobin's quaternary structure comes from its four subunits in roughly a tetrahedral arrangement.[34]

text: In most vertebrates, the hemoglobin molecule is an assembly of four globular protein subunits. Each subunit is composed of a protein chain tightly associated with a non-protein prosthetic heme group. Each protein chain arranges into a set of alpha-helix structural segments connected together in a globin fold arrangement. Such a name is given because this arrangement is the same folding motif used in other heme/globin proteins such as myoglobin.[36][37] This folding pattern contains a pocket that strongly binds the heme group.

text: A heme group consists of an iron (Fe) ion (charged atom) held in a heterocyclic ring, known as a porphyrin. This porphyrin ring consists of four pyrrole molecules cyclically linked together (by methine bridges) with the iron ion bound in the center.[38] The iron ion, which is the site of oxygen binding, coordinates with the four nitrogen atoms in the center of the ring, which all lie in one plane. The iron is bound strongly (covalently) to the globular protein via the N atoms of the imidazole ring of F8 histidine residue (also known as the proximal histidine) below the porphyrin ring. A sixth position can reversibly bind oxygen by a coordinate covalent bond,[39] completing the octahedral group of six ligands. Oxygen binds in an "end-on bent" geometry where one oxygen atom binds to Fe and the other protrudes at an angle. When oxygen is not bound, a very weakly bonded water molecule fills the site, forming a distorted octahedron.

text: Even though carbon dioxide is carried by hemoglobin, it does not compete with oxygen for the iron-binding positions but is bound to the protein chains of the structure.

text: The iron ion may be either in the Fe2+ or in the Fe3+ state, but ferrihemoglobin (methemoglobin) (Fe3+) cannot bind oxygen.[40] In binding, oxygen temporarily and reversibly oxidizes (Fe2+) to (Fe3+) while oxygen temporarily turns into the superoxide ion, thus iron must exist in the +2 oxidation state to bind oxygen. If superoxide ion associated to Fe3+ is protonated, the hemoglobin iron will remain oxidized and incapable of binding oxygen. In such cases, the enzyme methemoglobin reductase will be able to eventually reactivate methemoglobin by reducing the iron center.

text: In adult humans, the most common hemoglobin type is a tetramer (which contains four subunit proteins) called hemoglobin A, consisting of two α and two β subunits non-covalently bound, each made of 141 and 146 amino acid residues, respectively. This is denoted as α2β2. The subunits are structurally similar and about the same size. Each subunit has a molecular weight of about 16,000 daltons,[41] for a total molecular weight of the tetramer of about 64,000 daltons (64,458 g/mol).[42] Thus, 1 g/dL = 0.1551 mmol/L. Hemoglobin A is the most intensively studied of the hemoglobin molecules.

text: In human infants, the hemoglobin molecule is made up of 2 α chains and 2 γ chains. The gamma chains are gradually replaced by β chains as the infant grows.[43]

text: The four polypeptide chains are bound to each other by salt bridges, hydrogen bonds, and the hydrophobic effect.

text: Oxygen saturation[edit]

text: In general, hemoglobin can be saturated with oxygen molecules (oxyhemoglobin), or desaturated with oxygen molecules (deoxyhemoglobin).[44]

text: Oxyhemoglobin[edit]

text: Oxyhemoglobin is formed during physiological respiration when oxygen binds to the heme component of the protein hemoglobin in red blood cells. This process occurs in the pulmonary capillaries adjacent to the alveoli of the lungs. The oxygen then travels through the blood stream to be dropped off at cells where it is utilized as a terminal electron acceptor in the production of ATP by the process of oxidative phosphorylation. It does not, however, help to counteract a decrease in blood pH. Ventilation, or breathing, may reverse this condition by removal of carbon dioxide, thus causing a shift up in pH.[45]

text: Hemoglobin exists in two forms, a taut (tense) form (T) and a relaxed form (R). Various factors such as low pH, high CO2 and high 2,3 BPG at the level of the tissues favor the taut form, which has low oxygen affinity and releases oxygen in the tissues. Conversely, a high pH, low CO2, or low 2,3 BPG favors the relaxed form, which can better bind oxygen.[46] The partial pressure of the system also affects O2 affinity where, at high partial pressures of oxygen (such as those present in the alveoli), the relaxed (high affinity, R) state is favoured. Inversely, at low partial pressures (such as those present in respiring tissues), the (low affinity, T) tense state is favoured.[47] Additionally, the binding of oxygen to the iron(II) heme pulls the iron into the plane of the porphyrin ring, causing a slight conformational shift. The shift encourages oxygen to bind to the three remaining heme units within hemoglobin (thus, oxygen binding is cooperative).

text: Deoxygenated hemoglobin[edit]

text: Deoxygenated hemoglobin is the form of hemoglobin without the bound oxygen. The absorption spectra of oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has significantly lower absorption of the 660 nm wavelength than deoxyhemoglobin, while at 940 nm its absorption is slightly higher. This difference is used for the measurement of the amount of oxygen in a patient's blood by an instrument called a pulse oximeter. This difference also accounts for the presentation of cyanosis, the blue to purplish color that tissues develop during hypoxia.[48]

text: Deoxygenated hemoglobin is paramagnetic; it is weakly attracted to magnetic fields.[49][50] In contrast, oxygenated hemoglobin exhibits diamagnetism, a weak repulsion from a magnetic field.[50]

text: Evolution of vertebrate hemoglobin[edit]

text: Scientists agree that the event that separated myoglobin from hemoglobin occurred after lampreys diverged from jawed vertebrates.[51] This separation of myoglobin and hemoglobin allowed for the different functions of the two molecules to arise and develop: myoglobin has more to do with oxygen storage while hemoglobin is tasked with oxygen transport.[52] The α- and β-like globin genes encode the individual subunits of the protein.[23] The predecessors of these genes arose through another duplication event also after the gnathosome common ancestor derived from jawless fish, approximately 450–500 million years ago.[51] The development of α and β genes created the potential for hemoglobin to be composed of multiple subunits, a physical composition central to hemoglobin's ability to transport oxygen. Having multiple subunits contributes to hemoglobin's ability to bind oxygen cooperatively as well as be regulated allosterically.[52] Subsequently, the α gene also underwent a duplication event to form the HBA1 and HBA2 genes.[53] These further duplications and divergences have created a diverse range of α- and β-like globin genes that are regulated so that certain forms occur at different stages of development.[52]

text: Most ice fish of the family Channichthyidae have lost their hemoglobin genes as an adaptation to cold water.[5]

text: Iron's oxidation state in oxyhemoglobin[edit]

text: Assigning oxygenated hemoglobin's oxidation state is difficult because oxyhemoglobin (Hb-O2), by experimental measurement, is diamagnetic (no net unpaired electrons), yet the lowest-energy (ground-state) electron configurations in both oxygen and iron are paramagnetic (suggesting at least one unpaired electron in the complex). The lowest-energy form of oxygen, and the lowest energy forms of the relevant oxidation states of iron, are these:

text:
Triplet oxygen, the lowest-energy molecular oxygen species, has two unpaired electrons in antibonding π* molecular orbitals.
Iron(II) tends to exist in a high-spin 3d6 configuration with four unpaired electrons.
Iron(III) (3d5) has an odd number of electrons, and thus must have one or more unpaired electrons, in any energy state.

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text: All of these structures are paramagnetic (have unpaired electrons), not diamagnetic. Thus, a non-intuitive (e.g., a higher-energy for at least one species) distribution of electrons in the combination of iron and oxygen must exist, in order to explain the observed diamagnetism and no unpaired electrons.

text: The two logical possibilities to produce diamagnetic (no net spin) Hb-O2 are:

text:
Low-spin Fe2+ binds to singlet oxygen. Both low-spin iron and singlet oxygen are diamagnetic. However, the singlet form of oxygen is the higher-energy form of the molecule.
Low-spin Fe3+ binds to O2•− (the superoxide ion) and the two unpaired electrons couple antiferromagnetically, giving observed diamagnetic properties.  Here, the iron has been oxidized (has lost one electron), and the oxygen has been reduced (has gained one electron).

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text: Another possible model in which low-spin Fe4+ binds to peroxide, O22−, can be ruled out by itself, because the iron is paramagnetic (although the peroxide ion is diamagnetic). Here, the iron has been oxidized by two electrons, and the oxygen reduced by two electrons.

text: Direct experimental data:

text:
X-ray photoelectron spectroscopy suggests iron has an oxidation state of approximately 3.2.
Infrared vibrational frequencies of the O-O bond suggests a bond length fitting with superoxide (a bond order of about 1.6, with superoxide being 1.5).
X-ray Absorption Near Edge Structures at the iron K-edge. The energy shift of 5 eV between deoxyhemoglobin and oxyhemoglobin, as for all the methemoglobin species, strongly suggests an actual local charge closer to Fe3+ than Fe2+.[54][55][56]

text: Thus, the nearest formal oxidation state of iron in Hb-O2 is the +3 state, with oxygen in the −1 state (as superoxide .O2−). The diamagnetism in this configuration arises from the single unpaired electron on superoxide aligning antiferromagnetically with the single unpaired electron on iron (in a low-spin d5 state), to give no net spin to the entire configuration, in accordance with diamagnetic oxyhemoglobin from experiment.[57][58]

text: The second choice of the logical possibilities above for diamagnetic oxyhemoglobin being found correct by experiment, is not surprising: singlet oxygen (possibility #1) is an unrealistically high energy state.  Model 3 leads to unfavorable separation of charge (and does not agree with the magnetic data), although it could make a minor contribution as a resonance form. Iron's shift to a higher oxidation state in Hb-O2 decreases the atom's size, and allows it into the plane of the porphyrin ring, pulling on the coordinated histidine residue and initiating the allosteric changes seen in the globulins.

text: Early postulates by bio-inorganic chemists claimed that possibility #1 (above) was correct and that iron should exist in oxidation state II. This conclusion seemed likely, since the iron oxidation state III as methemoglobin, when not accompanied by superoxide .O2− to "hold" the oxidation electron, was known to render hemoglobin incapable of binding normal triplet O2 as it occurs in the air. It was thus assumed that iron remained as Fe(II) when oxygen gas was bound in the lungs. The iron chemistry in this previous classical model was elegant, but the required presence of the diamagnetic, high-energy, singlet oxygen molecule was never explained. It was classically argued that the binding of an oxygen molecule placed high-spin iron(II) in an octahedral field of strong-field ligands; this change in field would increase the crystal field splitting energy, causing iron's electrons to pair into the low-spin configuration, which would be diamagnetic in Fe(II). This forced low-spin pairing is indeed thought to happen in iron when oxygen binds, but is not enough to explain iron's change in size. Extraction of an additional electron from iron by oxygen is required to explain both iron's smaller size and observed increased oxidation state, and oxygen's weaker bond.

text: The assignment of a whole-number oxidation state is a formalism, as the covalent bonds are not required to have perfect bond orders involving whole electron transfer. Thus, all three models for paramagnetic Hb-O2 may contribute to some small degree (by resonance) to the actual electronic configuration of Hb-O2. However, the model of iron in Hb-O2 being Fe(III) is more correct than the classical idea that it remains Fe(II).

text: Cooperativity[edit]

text: When oxygen binds to the iron complex, it causes the iron atom to move back toward the center of the plane of the porphyrin ring (see moving diagram). At the same time, the imidazole side-chain of the histidine residue interacting at the other pole of the iron is pulled toward the porphyrin ring. This interaction forces the plane of the ring sideways toward the outside of the tetramer, and also induces a strain in the protein helix containing the histidine as it moves nearer to the iron atom. This strain is transmitted to the remaining three monomers in the tetramer, where it induces a similar conformational change in the other heme sites such that binding of oxygen to these sites becomes easier.

text: As oxygen binds to one monomer of hemoglobin, the tetramer's conformation shifts from the T (tense) state to the R (relaxed) state. This shift promotes the binding of oxygen to the remaining three monomer's heme groups, thus saturating the hemoglobin molecule with oxygen.[59]

text: In the tetrameric form of normal adult hemoglobin, the binding of oxygen is, thus, a cooperative process. The binding affinity of hemoglobin for oxygen is increased by the oxygen saturation of the molecule, with the first molecules of oxygen bound influencing the shape of the binding sites for the next ones, in a way favorable for binding. This positive cooperative binding is achieved through steric conformational changes of the hemoglobin protein complex as discussed above; i.e., when one subunit protein in hemoglobin becomes oxygenated, a conformational or structural change in the whole complex is initiated, causing the other subunits to gain an increased affinity for oxygen. As a consequence, the oxygen binding curve of hemoglobin is sigmoidal, or S-shaped, as opposed to the normal hyperbolic curve associated with noncooperative binding.

text: The dynamic mechanism of the cooperativity in hemoglobin and its relation with the low-frequency resonance has been discussed.[60]

text: Binding for ligands other than oxygen[edit]

text: Besides the oxygen ligand, which binds to hemoglobin in a cooperative manner, hemoglobin ligands also include competitive inhibitors such as carbon monoxide (CO) and allosteric ligands such as carbon dioxide (CO2) and nitric oxide (NO). The carbon dioxide is bound to amino groups of the globin proteins to form carbaminohemoglobin; this mechanism is thought to account for about 10% of carbon dioxide transport in mammals. Nitric oxide can also be transported by hemoglobin; it is bound to specific thiol groups in the globin protein to form an S-nitrosothiol, which dissociates into free nitric oxide and thiol again, as the hemoglobin releases oxygen from its heme site. This nitric oxide transport to peripheral tissues is hypothesized to assist oxygen transport in tissues, by releasing vasodilatory nitric oxide to tissues in which oxygen levels are low.[61]

text: Competitive[edit]

text: The binding of oxygen is affected by molecules such as carbon monoxide (for example, from tobacco smoking, exhaust gas, and incomplete combustion in furnaces). CO competes with oxygen at the heme binding site. Hemoglobin's binding affinity for CO is 250 times greater than its affinity for oxygen,[62] meaning that small amounts of CO dramatically reduce hemoglobin's ability to transport oxygen. Since carbon monoxide is a colorless, odorless and tasteless gas, and poses a potentially fatal threat, carbon monoxide detectors have become commercially available to warn of dangerous levels in residences. When hemoglobin combines with CO, it forms a very bright red compound called carboxyhemoglobin, which may cause the skin of CO poisoning victims to appear pink in death, instead of white or blue. When inspired air contains CO levels as low as 0.02%, headache and nausea occur; if the CO concentration is increased to 0.1%, unconsciousness will follow. In heavy smokers, up to 20% of the oxygen-active sites can be blocked by CO.

text: In similar fashion, hemoglobin also has competitive binding affinity for cyanide (CN−), sulfur monoxide (SO), and sulfide (S2−), including hydrogen sulfide (H2S). All of these bind to iron in heme without changing its oxidation state, but they nevertheless inhibit oxygen-binding, causing grave toxicity.

text: The iron atom in the heme group must initially be in the ferrous (Fe2+) oxidation state to support oxygen and other gases' binding and transport (it temporarily switches to ferric during the time oxygen is bound, as explained above). Initial oxidation to the ferric (Fe3+) state without oxygen converts hemoglobin into "hemiglobin" or methemoglobin, which cannot bind oxygen. Hemoglobin in normal red blood cells is protected by a reduction system to keep this from happening. Nitric oxide is capable of converting a small fraction of hemoglobin to methemoglobin in red blood cells. The latter reaction is a remnant activity of the more ancient nitric oxide dioxygenase function of globins.

text: Allosteric[edit]

text: Carbon dioxide occupies a different binding site on the hemoglobin. Carbon dioxide is more readily dissolved in deoxygenated blood, facilitating its removal from the body after the oxygen has been released to tissues undergoing metabolism. This increased affinity for carbon dioxide by the venous blood is known as the Haldane effect. Through the enzyme carbonic anhydrase, carbon dioxide reacts with water to give carbonic acid, which decomposes into bicarbonate and protons:

text: Hence, blood with high carbon dioxide levels is also lower in pH (more acidic). Hemoglobin can bind protons and carbon dioxide, which causes a conformational change in the protein and facilitates the release of oxygen. Protons bind at various places on the protein, while carbon dioxide binds at the α-amino group.[63] Carbon dioxide binds to hemoglobin and forms carbaminohemoglobin.[64] This decrease in hemoglobin's affinity for oxygen by the binding of carbon dioxide and acid is known as the Bohr effect. The Bohr effect favors the T state rather than the R state. (shifts the O2-saturation curve to the right). Conversely, when the carbon dioxide levels in the blood decrease (i.e., in the lung capillaries), carbon dioxide and protons are released from hemoglobin, increasing the oxygen affinity of the protein. A reduction in the total binding capacity of hemoglobin to oxygen (i.e. shifting the curve down, not just to the right) due to reduced pH is called the root effect. This is seen in bony fish.

text: It is necessary for hemoglobin to release the oxygen that it binds; if not, there is no point in binding it. The sigmoidal curve of hemoglobin makes it efficient in binding (taking up O2 in lungs), and efficient in unloading (unloading O2 in tissues).[65]

text: In people acclimated to high altitudes, the concentration of 2,3-Bisphosphoglycerate (2,3-BPG) in the blood is increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of lower oxygen tension. This phenomenon, where molecule Y affects the binding of molecule X to a transport molecule Z, is called a heterotropic allosteric effect. Hemoglobin in organisms at high altitudes has also adapted such that it has less of an affinity for 2,3-BPG and so the protein will be shifted more towards its R state. In its R state, hemoglobin will bind oxygen more readily, thus allowing organisms to perform the necessary metabolic processes when oxygen is present at low partial pressures.[66]

text: Animals other than humans use different molecules to bind to hemoglobin and change its O2 affinity under unfavorable conditions. Fish use both ATP and GTP. These bind to a phosphate "pocket" on the fish hemoglobin molecule, which stabilizes the tense state and therefore decreases oxygen affinity.[67] GTP reduces hemoglobin oxygen affinity much more than ATP, which is thought to be due to an extra hydrogen bond formed that further stabilizes the tense state.[68] Under hypoxic conditions, the concentration of both ATP and GTP is reduced in fish red blood cells to increase oxygen affinity.[69]

text: A variant hemoglobin, called fetal hemoglobin (HbF, α2γ2), is found in the developing fetus, and binds oxygen with greater affinity than adult hemoglobin. This means that the oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen tension), in comparison to that of adult hemoglobin. As a result, fetal blood in the placenta is able to take oxygen from maternal blood.

text: Hemoglobin also carries nitric oxide (NO) in the globin part of the molecule. This improves oxygen delivery in the periphery and contributes to the control of respiration. NO binds reversibly to a specific cysteine residue in globin; the binding depends on the state (R or T) of the hemoglobin. The resulting S-nitrosylated hemoglobin influences various NO-related activities such as the control of vascular resistance, blood pressure and respiration. NO is not released in the cytoplasm of red blood cells but transported  out of them by an anion exchanger called AE1.[70]

text: Types in humans[edit]

text: Hemoglobin variants are a part of the normal embryonic and fetal development. They may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Some well-known hemoglobin variants, such as sickle-cell anemia, are responsible for diseases and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants.[71][72]

text: In the embryo:

text:
Gower 1 (ζ2ε2)
Gower 2 (α2ε2) (PDB: 1A9W)
Hemoglobin Portland I (ζ2γ2)
Hemoglobin Portland II (ζ2β2).

text: In the fetus:

text: Hemoglobin F (α2γ2) (PDB: 1FDH).

text: After birth:

text:
Hemoglobin A (α2β2) (PDB: 1BZ0) – The most common with a normal amount over 95%
Hemoglobin A2 (α2δ2) – δ chain synthesis begins late in the third trimester and, in adults, it has a normal range of 1.5–3.5%
Hemoglobin F (α2γ2) – In adults Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease and beta-thalassemia.

text: Variant forms that cause disease:

text:
Hemoglobin D-Punjab – (α2βD2) – A variant form of hemoglobin.
Hemoglobin H (β4) – A variant form of hemoglobin, formed by a tetramer of β chains, which may be present in variants of α thalassemia.
Hemoglobin Barts (γ4) – A variant form of hemoglobin, formed by a tetramer of γ chains, which may be present in variants of α thalassemia.
Hemoglobin S (α2βS2) – A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the β-chain gene, causing a change in the properties of hemoglobin, which results in sickling of red blood cells.
Hemoglobin C (α2βC2) – Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
Hemoglobin E (α2βE2) – Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
Hemoglobin AS – A heterozygous form causing sickle cell trait with one adult gene and one sickle cell disease gene
Hemoglobin SC disease – A compound heterozygous form with one sickle gene and another encoding Hemoglobin C.
Hemoglobin Hopkins-2 - A variant form of hemoglobin that is sometimes viewed in combination with Hemoglobin S to produce sickle cell disease.

text: Degradation in vertebrate animals[edit]

text:
When red blood cells reach the end of their life due to aging or defects, they are removed from the circulation by the phagocytic activity of macrophages in the spleen or the liver or hemolyze within the circulation. Free hemoglobin is then cleared from the circulation via the hemoglobin transporter CD163, which is  exclusively expressed on monocytes or macrophages. Within these cells the hemoglobin molecule is broken up, and the iron gets recycled. This process also produces one molecule of carbon monoxide for every molecule of heme degraded.[73] Heme degradation is one of the few natural sources of carbon monoxide in the human body, and is responsible for the normal blood levels of carbon monoxide even in people breathing pure air. The other major final product of heme degradation is bilirubin. Increased levels of this chemical are detected in the blood if red blood cells are being destroyed more rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that has been released from the blood cells too rapidly can clog small blood vessels, especially the delicate blood filtering vessels of the kidneys, causing kidney damage.
Iron is removed from heme and salvaged for later use, it is stored as hemosiderin or ferritin in tissues and transported in plasma by beta globulins as transferrins. When the porphyrin ring is broken up, the fragments are normally secreted as a yellow pigment called bilirubin, which is secreted into the intestines as bile. Intestines metabolise bilirubin into urobilinogen. Urobilinogen leaves the body in faeces, in a pigment called stercobilin. Globulin is metabolised into amino acids that are then released into circulation.

text: Role in disease[edit]

text: Hemoglobin deficiency can be caused either by a decreased amount of hemoglobin molecules, as in anemia, or by decreased ability of each molecule to bind oxygen at the same partial pressure of oxygen. Hemoglobinopathies (genetic defects resulting in abnormal structure of the hemoglobin molecule)[74] may cause both. In any case, hemoglobin deficiency decreases blood oxygen-carrying capacity. Hemoglobin deficiency is, in general, strictly distinguished from hypoxemia, defined as decreased partial pressure of oxygen in blood,[75][76][77][78] although both are causes of hypoxia (insufficient oxygen supply to tissues).

text: Other common causes of low hemoglobin include loss of blood, nutritional deficiency, bone marrow problems, chemotherapy, kidney failure, or abnormal hemoglobin (such as that of sickle-cell disease).

text: The ability of each hemoglobin molecule to carry oxygen is normally modified by altered blood pH or CO2, causing an altered oxygen–hemoglobin dissociation curve. However, it can also be pathologically altered in, e.g., carbon monoxide poisoning.

text: Decrease of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of anemia. Anemia has many different causes, although iron deficiency and its resultant iron deficiency anemia are the most common causes in the Western world. As absence of iron decreases heme synthesis, red blood cells in iron deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic (smaller than normal). Other anemias are rarer. In hemolysis (accelerated breakdown of red blood cells), associated jaundice is caused by the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause renal failure.

text: Some mutations in the globin chain are associated with the hemoglobinopathies, such as sickle-cell disease and thalassemia. Other mutations, as discussed at the beginning of the article, are benign and are referred to merely as hemoglobin variants.

text: There is a group of genetic disorders, known as the porphyrias that are characterized by errors in metabolic pathways of heme synthesis. King George III of the United Kingdom was probably the most famous porphyria sufferer.

text: To a small extent, hemoglobin A slowly combines with glucose at the terminal valine (an alpha aminoacid) of each β chain. The resulting molecule is often referred to as Hb A1c, a glycosylated hemoglobin. The binding of glucose to amino acids in the hemoglobin takes place spontaneously (without the help of an enzyme) in many proteins, and is not known to serve a useful purpose. However, as the concentration of glucose in the blood increases, the percentage of Hb A that turns into Hb A1c increases. In diabetics whose glucose usually runs high, the percent Hb A1c also runs high. Because of the slow rate of Hb A combination with glucose, the Hb A1c percentage reflects a weighted average of blood glucose levels over the lifetime of red cells, which is approximately 120 days.[79] The levels of glycosylated hemoglobin are therefore measured in order to monitor the long-term control of the chronic disease of type 2 diabetes mellitus (T2DM). Poor control of T2DM results in high levels of glycosylated hemoglobin in the red blood cells. The normal reference range is approximately 4.0–5.9%. Though difficult to obtain, values less than 7% are recommended for people with T2DM. Levels greater than 9% are associated with poor control of the glycosylated hemoglobin, and levels greater than 12% are associated with very poor control. Diabetics who keep their glycosylated hemoglobin levels close to 7% have a much better chance of avoiding the complications that may accompany diabetes (than those whose levels are 8% or higher).[80] In addition, increased glycosylation of hemoglobin increases its affinity for oxygen, therefore preventing its release at the tissue and inducing a level of hypoxia in extreme cases.[81]

text: Elevated levels of hemoglobin are associated with increased numbers or sizes of red blood cells, called polycythemia. This elevation may be caused by congenital heart disease, cor pulmonale, pulmonary fibrosis, too much erythropoietin, or polycythemia vera.[82] High hemoglobin levels may also be caused by exposure to high altitudes, smoking, dehydration (artificially by concentrating Hb), advanced lung disease and certain tumors.[43]

text: A recent study done in Pondicherry, India, shows its importance in coronary artery disease.[83]

text: Diagnostic uses[edit]

text: Hemoglobin concentration measurement is among the most commonly performed blood tests, usually as part of a complete blood count. For example, it is typically tested before or after blood donation. Results are reported in g/L, g/dL or mol/L. 1 g/dL equals about 0.6206 mmol/L, although the latter units are not used as often due to uncertainty regarding the polymeric state of the molecule.[84] This conversion factor, using the single globin unit molecular weight of 16,000 Da, is more common for hemoglobin concentration in blood. For MCHC (mean corpuscular hemoglobin concentration) the conversion factor 0.155, which uses the tetramer weight of 64,500 Da, is more common.[85] Normal levels are:

text:
Men: 13.8 to 18.0 g/dL (138 to 180 g/L, or 8.56 to 11.17 mmol/L)
Women: 12.1 to 15.1 g/dL (121 to 151 g/L, or 7.51 to 9.37 mmol/L)
Children: 11 to 16 g/dL (110 to 160 g/L, or 6.83 to 9.93 mmol/L)
Pregnant women: 11 to 14 g/dL (110 to 140 g/L, or 6.83 to 8.69 mmol/L) (9.5 to 15 usual value during pregnancy)[86][87]

text: Normal values of hemoglobin in the 1st and 3rd trimesters of pregnant women must be at least 11 g/dL and at least 10.5 g/dL during the 2nd trimester.[88]

text: Dehydration or hyperhydration can greatly influence measured hemoglobin levels. Albumin can indicate hydration status.

text: If the concentration is below normal, this is called anemia. Anemias are classified by the size of red blood cells, the cells that contain hemoglobin in vertebrates. The anemia is called "microcytic" if red cells are small, "macrocytic" if they are large, and "normocytic" otherwise.

text: Hematocrit, the proportion of blood volume occupied by red blood cells, is typically about three times the hemoglobin concentration measured in g/dL. For example, if the hemoglobin is measured at 17 g/dL, that compares with a hematocrit of 51%.[89]

text: Laboratory hemoglobin test methods require a blood sample (arterial, venous, or capillary) and analysis on hematology analyzer and CO-oximeter. Additionally, a new noninvasive hemoglobin (SpHb) test method called Pulse CO-Oximetry is also available with comparable accuracy to invasive methods.[90]

text: Concentrations of oxy- and deoxyhemoglobin can be measured continuously, regionally and noninvasively using NIRS.[91][92][93][94][95] NIRS can be used both on the head and on muscles. This technique is often used for research in e.g. elite sports training, ergonomics, rehabilitation, patient monitoring, neonatal research, functional brain monitoring, brain computer interface, urology (bladder contraction), neurology (Neurovascular coupling) and more.

text: Long-term control of blood sugar concentration can be measured by the concentration of Hb A1c. Measuring it directly would require many samples because blood sugar levels vary widely through the day. Hb A1c is the product of the irreversible reaction of hemoglobin A with glucose. A higher glucose concentration results in more Hb A1c. Because the reaction is slow, the Hb A1c proportion represents glucose level in blood averaged over the half-life of red blood cells, is typically 50–55 days. An Hb A1c proportion of 6.0% or less show good long-term glucose control, while values above 7.0% are elevated. This test is especially useful for diabetics.[96]

text: The functional magnetic resonance imaging (fMRI) machine uses the signal from deoxyhemoglobin, which is sensitive to magnetic fields since it is paramagnetic. Combined measurement with NIRS shows good correlation with both the oxy- and deoxyhemoglobin signal compared to the BOLD signal.[97]

text: Athletic tracking and self tracking uses[edit]

text:
Hemoglobin can be tracked noninvasively, to build an individual data set tracking the hemoconcentration and hemodilution effects of daily activities for better understanding of sports performance and training. Athletes are often concerned about endurance and intensity of exercise.  The sensor uses light-emitting diodes that emit red and infrared light through the tissue to a light detector, which then sends a signal to a processor to calculate the absorption of light by the hemoglobin protein.[98]
This sensor is similar to a pulse oximeter, which consists of a small sensing device that clips to the finger.

text: Analogues in non-vertebrate organisms[edit]

text: A variety of oxygen-transport and -binding proteins exist in organisms throughout the animal and plant kingdoms. Organisms including bacteria, protozoans, and fungi all have hemoglobin-like proteins whose known and predicted roles include the reversible binding of gaseous ligands. Since many of these proteins contain globins and the heme moiety (iron in a flat porphyrin support), they are often called hemoglobins, even if their overall tertiary structure is very different from that of vertebrate hemoglobin. In particular, the distinction of "myoglobin" and hemoglobin in lower animals is often impossible, because some of these organisms do not contain muscles. Or, they may have a recognizable separate circulatory system but not one that deals with oxygen transport (for example, many insects and other arthropods). In all these groups, heme/globin-containing molecules (even monomeric globin ones) that deal with gas-binding are referred to as oxyhemoglobins. In addition to dealing with transport and sensing of oxygen, they may also deal with NO, CO2, sulfide compounds, and even O2 scavenging in environments that must be anaerobic.[99] They may even deal with detoxification of chlorinated materials in a way analogous to heme-containing P450 enzymes and peroxidases.

text: The structure of hemoglobins varies across species. Hemoglobin occurs in all kingdoms of organisms, but not in all organisms. Primitive species such as bacteria, protozoa, algae, and plants often have single-globin hemoglobins. Many nematode worms, molluscs, and crustaceans contain very large multisubunit molecules, much larger than those in vertebrates. In particular, chimeric hemoglobins found in fungi and giant annelids may contain both globin and other types of proteins.[13]

text: One of the most striking occurrences and uses of hemoglobin in organisms is in the giant tube worm (Riftia pachyptila, also called Vestimentifera), which can reach 2.4 meters length and populates ocean volcanic vents. Instead of a digestive tract, these worms contain a population of bacteria constituting half the organism's weight. The bacteria react with H2S from the vent and O2 from the water to produce energy to make food from H2O and CO2. The worms end with a deep-red fan-like structure ("plume"), which extends into the water and absorbs H2S and O2 for the bacteria, and CO2 for use as synthetic raw material similar to photosynthetic plants. The structures are bright-red due to their containing several extraordinarily complex hemoglobins that have up to 144 globin chains, each including associated heme structures. These hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and even to carry sulfide, without being completely "poisoned" or inhibited by it as hemoglobins in most other species are.[100][101]

text: Other oxygen-binding proteins[edit]

text: Presence in nonerythroid cells[edit]

text: Some nonerythroid cells (i.e., cells other than the red blood cell line) contain hemoglobin. In the brain, these include the A9 dopaminergic neurons in the substantia nigra, astrocytes in the cerebral cortex and hippocampus, and in all mature oligodendrocytes.[12] It has been suggested that brain hemoglobin in these cells may enable the "storage of oxygen to provide a homeostatic mechanism in anoxic conditions, which is especially important for A9 DA neurons that have an elevated metabolism with a high requirement for energy production".[12] It has been noted further that "A9 dopaminergic neurons may be at particular risk since in addition to their high mitochondrial activity they are under intense oxidative stress caused by the production of hydrogen peroxide via autoxidation and/or monoamine oxidase (MAO)-mediated deamination of dopamine and the subsequent reaction of accessible ferrous iron to generate highly toxic hydroxyl radicals".[12] This may explain the risk of these cells for degeneration in Parkinson's disease.[12] The hemoglobin-derived iron in these cells is not the cause of the post-mortem darkness of these cells (origin of the Latin name, substantia nigra), but rather is due to neuromelanin.

text: Outside the brain, hemoglobin has non-oxygen-carrying functions as an antioxidant and a regulator of iron metabolism in macrophages,[102] alveolar cells,[103] and mesangial cells in the kidney.[104]

text: In history, art and music[edit]

text: Historically, an association between the color of blood and rust occurs in the association of the planet Mars, with the Roman god of war, since the planet is an orange-red, which reminded the ancients of blood. Although the color of the planet is due to iron compounds in combination with oxygen in the Martian soil, it is a common misconception that the iron in hemoglobin and its oxides gives blood its red color. The color is actually due to the porphyrin moiety of hemoglobin to which the iron is bound, not the iron itself,[105] although the ligation and redox state of the iron can influence the pi to pi* or n to pi* electronic transitions of the porphyrin and hence its optical characteristics.

text: Artist Julian Voss-Andreae created a sculpture called "Heart of Steel (Hemoglobin)" in 2005, based on the protein's backbone. The sculpture was made from glass and weathering steel. The intentional rusting of the initially shiny work of art mirrors hemoglobin's fundamental chemical reaction of oxygen binding to iron.[106][107]

text: Montreal artist Nicolas Baier created Lustre (Hémoglobine), a sculpture in stainless steel that shows the structure of the hemoglobin molecule. It is displayed in the atrium of McGill University Health Centre's research centre in Montreal. The sculpture measures about 10 metres × 10 metres × 10 metres.[108][109]


document_title: Remedial education

question_text: who is most likely to be referred for remedial reading instruction

text: Remedial education

text: In Canada[edit]

text: In Canada, the process whereby mature students take secondary school courses so that they can qualify to take post-secondary education is called academic upgrading. The Workers' Compensation Board of Nova Scotia defines academic upgrading as "programs offered to adult learners who require the academic pre-requisites needed for entry into many occupational programs."[1] The Alberta Ministry of Enterprise and Advanced Education advises that academic upgrading can be pursued through a post-secondary institution, a school board program such as a storefront school, or via distance learning.[2]

text: In the United States[edit]

text: Post secondary remediation is delivered on both 2-year community college and 4-year university campuses in the U.S. The bulk of remedial courses focus on advancing underprepared students' literacy skills (English and reading) or math skills.[3] However, remedial courses can also be offered for other subjects such as science or study skills.[4]

text: Student placement[edit]

text: Many students are placed into remedial courses through placement tests such as the ACT, SAT, ACCUPLACER, or COMPASS assessments. Often, each college or university sets its own score thresholds for determining whether a student must enroll in remedial courses. However, some states are moving toward a uniform standard for remedial placement cut scores. Students are required to enroll in remedial courses before advancing to a college level course in that subject. Colleges review a student's score by subject - math, English, science, etc. - and compare that score to the school's cutoff.[5] For example, a college might use a score of 19 on the ACT math section as the threshold for determining whether a student must enroll in a remedial math course or college-level math course.

text: Particularly at community colleges – which are open enrollment to any student with a high school degree or GED – multiple semesters of remedial coursework may be available to and required of students that enter with low placement test scores.

text: Whether placement tests are the most effective method of placing students is an open debate across the US. Some colleges and states are experimenting with using high school GPA and placement test scores to determine student course referral.[5] A study of placement tests by the Community College Research Center in 2012 found: Placement test scores are not especially good predictors of course grades in developmental education classes. More importantly, the tests do not have much explanatory power across a range of measures of performance including college GPA, credit accumulation, and success in gatekeeper English and math classes. Using GPA with standardized test scores may also improve the accuracy of remedial placement and limit the likelihood of placing students into additional remedial courses they may not need. North Carolina recently implemented a statewide policy that allows two-year colleges to use both placement test scores and high school GPA to place students.[6]

text: Student enrollment[edit]

text: Estimates on the portion of students in higher education taking remedial courses vary. At two-year colleges the percentage reported of students taking at least 1 remedial course varies from 41% to as high as 60%,.[7][8] Students from low-income households, African American students and Hispanic students are more likely to enroll in remedial courses.[7] National estimates show that among two-year college students, students age 17-19 are most likely to enroll in remedial courses followed by students age 20-24 and then students age 25+.[9]

text: The likelihood of remedial placement varies among states because of high school preparation, student demographics and state policies for assessing and placing students in remedial courses. Previous proportions of recent high school graduates enrolling in remedial courses at two-year colleges range from over 70% in Tennessee to 31% in North Carolina.[10] The proportion of students enrolling in remedial courses on public, four-year college campuses is generally lower ranging from 35% in South Dakota to 5% in Washington state.[11]

text: The state of Colorado issued a 2012 report on remedial placement showing that 40% of recent high school students enrolled in remedial courses at both two-year and 4- year colleges. Sixty-six (66%)of students enrolled in a two-year college and 24% of students at a four-year institution needed remediation.[12]

text: Educators and researchers also question whether many of the students directed into remediation ultimately need the course work, and some studies have found that the current method of using placement tests to assign students to remedial courses may be related to over placement.[13]

text: Course delivery[edit]

text: There is an active debate on how remedial courses should be delivered to students. Students that are placed into remedial courses hold differing skill levels and needs for support. There is an active debate on whether students that are on the upper end of the skill spectrum may be most successful bypassing remedial coursework and enrolling in college-level courses with additional tutoring (see National Efforts to Strengthen Remediation). In contrast, students with larger skill deficiencies may require substantial math and English instruction before they can succeed academically. Researchers continue to investigate and make recommendations for effective remedial education models.

text: Currently, remedial education courses are delivered many ways across the United States:

text:
Traditional, semester-long courses;
Cohort models that group a class of students together in a series of remedial courses;
Placing students in college-level courses with mandated tutoring or supplementary instruction;
Modularized courses that target particularly student skills;
Intensive, compressed courses that accelerate student readiness;
Courses that integrate remedial content with occupational skills;
Self-guided computer based courses that adapt to student skill deficiencies;
Online, in computer-based, traditional semester model.

text: In 2011, MDRC did a review of studies on remedial education delivery and found: "Programs that show the greatest benefits with relatively rigorous documentation either mainstream developmental students into college-level courses with additional supports, provide modularized or compressed courses to allow remedial students to more quickly complete their developmental work, or offer contextualized remedial education within occupational and vocational programs.[14]"

text: Accelerating the pace at which students progress through remedial courses is a reform now regularly highlighted in academic research and advocacy as effective for increasing student success. Often, remedial courses do not count toward a student's graduation requirements and taking many semesters of remedial education can lengthen a student's path to graduation and take up much needed financial aid. The Community College Research Center has found that accelerating a student's remedial English requirements resulted a higher likelihood of students completing their remedial sequences, a higher likelihood of enrolling in college-level English courses and a higher likelihood of students receiving a 'C' or better in the college-level course.[15]

text: Online Courses: Some colleges have explored the use of providing remedial education courses online for students; however, evidence indicates that completion of online remedial courses is lower across almost every group of students compared to in-person remedial instruction.[16] There is also evidence that students enrolling in online remedial education are less likely than their in-person counterparts to continue on to college-level coursework in the same subject.[17]

text: The methods for delivering remedial education and whether to deliver remedial education are active debates in the U.S. As Bahr (Bahr 2008a, pp. 420–421) explains, "On one hand, it fills an important niche in U.S. higher education by providing opportunities to rectify disparities generated in primary education and secondary schooling, to develop the minimum skills deemed necessary for functional participation in the economy and the democracy, and to acquire the prerequisite competencies that are crucial for negotiating college-level coursework. On the other hand, critics argue that taxpayers should not be required to pay twice for the same educational opportunities, that remediation diminishes academic standards and devalues post-secondary credentials, and that the large number of underprepared students entering colleges and universities demoralizes faculty. Following from these critiques, some have argued for a major restructuring of remediation or even the elimination of remedial programs altogether."

text: Research on outcomes[edit]

text: Depending on their skill level upon entering college, students can spend from 1 to multiple semesters working to fulfill remedial requirements before advancing to college level courses required for their degree. An example of a full sequence of math remedial courses for low-skill students might include: 1) Pre-Collegiate Math, 2) Basic Algebra, and 3) Intermediate Algebra.[18] There are many questions about how this structure both benefits students by increasing their preparation and harms students by increasing the courses required and time needed to complete college. Thomas Bailey from the Community College Research Center describes this in a 2010 report: For example, those with the greatest need for developmental math may be expected to enroll in and pass pre-collegiate math or arithmetic, basic algebra, and intermediate algebra, in order to prepare them forcollege-level algebra.[18]

text: Complete College America, a national non-profit working on remedial education reform, reports that among remedial students at two-year colleges 62% complete their remedial course and 23% complete associated college-level courses in that subject within 2 year (for example, complete math remediation and the college-level math requirements for their degree). On 4-year college campuses, 74% of students in remedial courses complete the course, and 37% complete remediation and an associated college-level course in that subject within 2 years.[9] The same report projects that 9.5% of two-year college students starting in remediation will graduate within 3 years, and 35.1% of 4-year college students starting in remedial courses will graduate within 6 years.

text: Similarly, a nationwide study of two year college students participating in remedial education found 46% of students referred to remedial reading and 33% of students in math remediation completed their remedial sequence. A substantial portion of these non-completing students – 29% in math and 16% in reading – did so because they did not pass their remedial course.[18] Another 11% of math students and 9% of reading students exited college without ever having failed or completed a remedial course. Students that enrolled in college and were placed into a sequence of 3 or more remedial courses were the least likely to persist to a college-level course. Like in all education pathways, there are many different points at which remedial students can step out of education. Research from the Community College Research Center at Colombia University suggests that many students do not complete their remedial sequences or do not enroll in the first college-level course in that subject.

text: National efforts[edit]

text: Over the last several years, a large amount of philanthropic and research attention has been directed at remedial education programs. Often, focus on remedial education is directed at 1) increasing the successful completion of remedial sequences 2) increasing the overall number of students with college degrees and certificates in the US and 3) decreasing the cost of remedial education to colleges and states.

text: Complete College America[edit]

text: A national non-profit organization, Complete College America (CCA), was established in 2009 and looks at paths to improving higher education outcomes for all students. The organization has provided large amounts of national data on the proportion of students enrolled in remedial courses across demographic groups. The organization has also worked with states to set goals for increasing college completion and making adjustments to higher education policies. Currently, CCA heavily promotes enrolling more students directly into college-level courses even though they would traditionally test into remedial courses. The organization also heavily promotes better aligning remedial courses with college-level courses, and using diverse measures of student academic standing for remedial placement.[19]

text: Achieving the Dream[edit]

text: Originally an initiative led by the Lumina Foundation, Achieving the Dream focuses on increasing the success of college students – particularly students of color and students from low-income backgrounds. Starting in 2004 the project funded promising, data driven approaches to strengthening remedial education coursework. Today, Achieving the Dream is its own, national organization with the same driving mission: "Achieving the Dream is a national reform network dedicated to community college student success and completion; focused primarily on helping low-income students and students of color complete their education and obtain market-valued credentials." The organization continues to fund positive interventions that move underprepared students through remediation with greater success and features a list of best practices and exemplary colleges from which other higher education administrators can learn. Achieving the Dream promotes many different promising interventions that can increase the success of students including: first-year student success courses that provide students with the skills to navigate college expectations/academics more effectively, accelerated remedial courses in math and English, student mentoring and coaching, mandatory orientations for new students and supplementary computer tutoring for remedial students.[20] Achieving the Dream also takes an active role in state policy advocacy and is currently working in 15 states to strengthen student remedial success.[21]

text: Core Principles Statement[edit]

text: In December 2012, The Dana Center at the University of Texas, Complete College America, Education Commission of the States, and Jobs for the Future released "Core Principles for Transforming Remedial Education: A Joint Statement" with 7 key principles for strengthening community college remedial programs. The statement's principles included: aligning remedial courses with a student's long-term area of study at the college, using multiple measures to placement students in remedial courses, requiring all students –including under-prepared students– to pick a program of study when they enter college, integrating academic support services into pre college-level coursework, creating accelerated course models with students with larger skill deficiencies, and measuring completion of remedial courses.[22]

text: Strategies that accelerate students through remedial coursework and on to college-level (also called gatekeeper) courses are widely promoted as one path to increasing the success of under-prepared students.[18]

text: Changes in North Carolina[edit]

text: In 2012, North Carolina underwent a wide scale redesign of their remedial education programs.[23] Branded as 'Success NC', the program's Developmental Education Initiative takes steps to redesign math and reading curricula, move students through remedial courses faster and better assess and place students. NC colleges can now incorporate high school grades into their course placement decisions. Additionally, starting in 2014, all colleges will deliver remedial reading & English in 3 shorter, 8 week modules for some students while allowing higher level remedial students to enroll in college-level English courses with required supplementary English instruction.[23]

text: Gates Foundation and Lumina Foundation[edit]

text: In 2009 the Bill and Melinda Gates Foundation appropriated $16.5 million to 15 colleges in 5 states to promote promising interventions in the remedial education.[24] Fueled by the broader goal of increasing the number of college graduates nationwide, the Gates Foundation promoted remedial interventions that proved successful, particularly low-income students and students of color, through the Lumina Foundation's Achieving the Dream Initiative.[25] A host of findings, recommendations and best practices -including 25 Steps to Effective Remedial Education- from the Gates Foundation and Lumina Foundation investments are now available through the Development Education Initiative through Achieving the Dream.[26]

text: In Europe[edit]

text: While remedial programmes are common in the United States, they are less common in Europe. Nevertheless, several European higher education institutes have started to offer remedial education programmes as well.[27] One of the reasons why European universities are starting to develop remedial courses is the different situation in the two continents. In the United States, a common assumption is that remediation attracts underprepared students of low socioeconomic status. Inadequate academic preparation is no longer a barrier to college access. In contrast, in Europe, a large part of the transitional problems are caused by differences among national secondary educational programmes, which are determined on a national level.[28] Therefore, these students are hindered to effectively start a bachelor or master programme. Remedial or developmental courses can help to bridge the gap.

text: European Framework of Transitional Preparatory/Remedial Teaching[edit]

text: To be able to compare and assess various preparatory courses in Europe, a European framework of transitional courses is necessary. By developing European Framework for Transitional Preparatory Courses (EFTPC), teachers around Europe can see how their design of their courses fit with the framework. In addition, potential improvements are identified and can be extended with the insights from the field. By using the WIKI technology, each teacher can add his/her suggestions to the EFTPC. This Framework is being developed in frame of European project STEP (Studies on Transitional Electronic Programmes) [1].

text: In Asia[edit]

text: Taiwan and China[edit]

text: Remedial education, also known as "buxiban" (simplified Chinese: 补习班; traditional Chinese: 補習班; pinyin: bǔxíbān, lit. "remedial education classes") are cram schools in Taiwan and China.

text: It is a prevalent belief that parents should send their children to all kinds of cram schools in order for their children to remain competitive with their peers of the same age. As a result, many children of school-going age in Mainland China or Taiwan have schedules packed with all sorts of remediation from cram school.

text: Buxiban teach a variety of subjects, including math, Chinese characters, and English as a foreign language. Studying at several buxiban is widely perceived as necessary to get a high-enough college entrance exam score to attend prestigious universities.

text: Some buxiban are located in English-speaking countries. Most of those in North America are operated by the local communities. There, they are equivalent to hoshū jugyō kō (hoshūkō) in ethnic Japanese communities and hagwon in ethnic Korean communities. Buxiban began appearing in North America in the 1880s.[29]


document_title: The Warrior (song)

question_text: who wrote the song i am the warrior

question_tokens: who wrote the song i am the warrior

text: The Warrior (song)

text: This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (March 2015) (Learn how and when to remove this template message)

tag: table

text:
"The Warrior"

Single by Scandal

from the album Warrior

Released
August 1984

Format
7" single

Recorded
1984

Genre
AOR, rock

Length
3:59

Label
Columbia

Songwriter(s)
Nick Gilder, Holly Knight

Producer(s)
Mike Chapman

Scandal singles chronology

"Win Some, Lose Some"
(1983)
"The Warrior"
(1984)
"Hands Tied"
(1984)

"Win Some, Lose Some"
(1983)
"The Warrior"
(1984)
"Hands Tied"
(1984)

text: "The Warrior" is a song by American rock band Scandal, from the album Warrior. The song was written by Holly Knight ("Love Is a Battlefield") and Nick Gilder ("Hot Child in the City"). The song went to number one in Canada and number seven in the United States, as well as number one on the Mainstream Rock chart in the US, in addition to winning a BMI Airplay Award in 1984. The music video of the song depicts the apocalypse in a warehouse.

text: Charts[edit]

text:
Chart (1984-1985)
Peak
position

Australia (Kent Music Report)[1]
6

Canadian RPM Top Singles
1

New Zealand RIANZ Top 40
11

UK Singles Chart
86

US Billboard Hot 100
7

US Billboard Album Rock Tracks
1


document_title: Public sector undertakings in India

question_text: how many navratna companies are there in india

text: Public sector undertakings in India

text: History[edit]

text: When India achieved independence in 1947, India was primarily an agricultural country with a weak industrial base. The national consensus was in favour of rapid industrialisation of the economy which was seen as the key to economic development, improving living standards and economic sovereignty.[1] Building upon the Bombay Plan, which noted the requirement of government intervention and regulation, the first Industrial Policy Resolution announced in 1948 laid down broad contours of the strategy of industrial development. Subsequently, the Planning Commission was constituted in March 1950 and the Industrial (Development and Regulation) Act was enacted in 1951 with the objective of empowering the government to take necessary steps to regulate industrial development.[2] Prime Minister Jawaharlal Nehru promoted an economic policy based on import substitution industrialisation and advocated a mixed economy.[3] He believed that the establishment of basic and heavy industry was fundamental to the development and modernisation of the Indian economy. India's second five year plan (1956–60) and the Industrial Policy Resolution of 1956 emphasised the development of public sector enterprises to meet Nehru's national industrialisation policy. Indian statistician Prasanta Chandra Mahalanobis was instrumental to its formulation, which was subsequently termed the Feldman–Mahalanobis model.[4][5]

text: The major consideration for the setting up of PSUs was to accelerate the growth of core sectors of the economy; to serve the equipment needs of strategically important sectors, and to generate employment and income. A large number of "sick units" were taken over from the private sector. Additionally, Indira Gandhi's government nationalised fourteen of India's largest private banks in 1969, and an additional six in 1980. This government-led industrial policy, with corresponding restrictions on private enterprise, was the dominant pattern of Indian economic development until the 1991 Indian economic crisis.[2] After the crisis, the government began dis-investing its ownership of several PSUs to raise capital and privatise companies facing poor financial performance and low efficiency.[6][7]

text: Governance[edit]

text: Many private have been awarded additional financial autonomy. These companies are "public sector companies that have comparative advantages", giving them greater autonomy to compete in the global market so as to "support [them] in their drive to become global giants".[8] Financial autonomy was initially awarded to nine PSUs as Navratna status in 1997.[9] Originally, the term Navaratna meant a talisman composed of nine precious gems. Later, this term was adopted in the courts of Gupta emperor Vikramaditya and Mughal emperor Akbar, as the collective name for nine extraordinary courtiers at their respective courts.

text: In 2010, the government established the higher Maharatna category, which raises a company's investment ceiling from Rs. 1,000 crore to Rs. 5,000 crore.[10] The Maharatna firms can now decide on investments of up to 15 per cent of their net worth in a project while the Navaratna companies could invest up to Rs 1,000 crore without explicit government approval. Two categories of "Miniratnas" afford less extensive financial autonomy.

text: Guidelines for awarding Ratna[11] status are as follow:

text:
Maharatna
Navratna
Miniratna Category-I
Miniratna Category-II

Eligibility
Three years with an average annual net profit of over Rs. 5000 crore, OR
Average annual Net worth of Rs. 10,000 crore for 3 years, OR Average annual Turnover of Rs. 20,000 crore for 3 years (against Rs 25,000 crore prescribed earlier)[12]

A score of 60 (out of 100), based on six parameters which include net profit, net worth, total manpower cost, total cost of production, cost of services, PBDIT (Profit Before Depreciation, Interest and Taxes), capital employed, etc., AND
A company must first be a Miniratna and have 4 independent directors on its board before it can be made a Navratna.

Have made profits continuously for the last three years or earned a net profit of Rs. 30 crore or more in one of the three years
Have made profits continuously for the last three years and should have a positive net worth.

Benefits for investment
Rs. 1,000 crore - Rs. 5,000 crore, or free to decide on investments up to 15% of their net worth in a project
up to Rs. 1,000 crore or 15% of their net worth on a single project or 30% of their net worth in the whole year (not exceeding Rs. 1,000 crores).
up to Rs. 500 crore or equal to their net worth, whichever is lower.
up to Rs. 300 crore or up to 50% of their net worth, whichever is lower.

text: PSUs in India are also categorised based on their special non-financial objectives and are registered under Section 8 of Companies Act, 2013 (erstwhile Section 25 of Companies Act, 1956).

text: List of Public Sector Undertakings[edit]

text: As on 13 September 2017 there are 8 Maharatnas, 16 Navratnas and 74 Miniratnas.[13]There are nearly 300 CPSEs(central public sector enterprises) in total.[14]

text: List of Maharatna

text:
National Thermal Power Corporation(NTPC)
Oil and Natural Gas Corporation(ONGC)
Steel Authority of India Limited(SAIL)
Bharat Heavy Electricals Limited(BHEL)
Indian Oil Corporation Limited(IOCL)
Coal India Limited(CIL)
Gas Authority of India Limited(GAIL)
Bharat Petroleum Corporation Limited(BPCL)

text: List of Navratna

text:
Bharat Electronics Limited (BEL)
Container Corporation of India (CONCOR)
Engineers India Limited (EIL)
Hindustan Aeronautics Limited (HAL)
Hindustan Petroleum (HPCL)
Mahanagar Telephone Nigam Limited (MTNL)
National Aluminium Company (NALCO)
National Buildings Construction Corporation (NBCC)
National Mineral Development Corporation (NMDC)
Neyveli Lignite Corporation
Oil India Limited (OIL)
Power Finance Corporation
Power Grid Corporation of India Limited
Rashtriya Ispat Nigam Limited
Rural Electrification Corporation
Shipping Corporation of India (SCI)

text: List of Miniratna-I

text:
Airports Authority of India (AAI)
Antrix Corporation
Balmer Lawrie
Bharat Coking Coal Limited
Bharat Dynamics Limited
Bharat Earth Movers
Bharat Sanchar Nigam Limited (BSNL)
Bridge and Roof
Central Warehousing Corporation
Central Coalfields Limited
Chennai Petroleum Corporation
Cochin Shipyard
Dredging Corporation of India
Educational Consultants India
Kamarajar Port
Garden Reach Shipbuilders & Engineers
Goa Shipyard
Hindustan Copper
HLL Lifecare
Hindustan newsprint
Hindustan Paper
Housing and Urban Development Corporation
HSCC
India Tourism Development Corporation
India Trade Promotion Organisation
Indian Rare Earths
Indian Railway Catering and Tourism Corporation
Indian Renewable Energy Development Agency
Ircon International
Kudremukh Iron Ore Company
Mazagaon Dock Limited
Mahanadi Coalfields
MOIL
Mangalore Refinery and Petrochemicals Limited
Mishra Dhatu Nigam
MMTC Ltd.
MSTC Ltd.
National Fertilizers
National Small Industries Corporation Limited
National Seeds Corporation
NHPC Ltd.
Northern Coalfields
North Eastern Electric Power Corporation Limited
Numaligarh Refinery
ONGC Videsh
Pawan Hans
Projects and Development India Limited
RailTel Corporation of India
Rail Vikas Nigam Limited
Rashtriya Chemicals & Fertilizers
RITES
SJVN Ltd.
Security Printing and Minting Corporation of India
South Eastern Coalfields
State Trading Corporation of India
Telecommunications Consultants India
THDC Ltd.
Western Coalfields
Water and Power Consultancy Services

text: List of Miniratna-II

text:
Artificial Limbs Manufacturing Corporation of India
Bharat Pumps & Compressors
Broadcast Engineering Consultants India
Central Mine Planning and Design Institute
Central Railside Warehouse Company
Engineering Projects
FCI Aravali Gypsum and Minerals (India) Limited
Ferro Scrap Nigam Limited
HMT (International) Ltd.
Indian Medicines & Pharmaceuticals Corporation Limited
MECON
Mineral Exploration Corporation Limited
National Film Development Corporation of India
PEC Ltd.
Rajasthan Electronics & Instruments Limited


document_title: List of hills in the Peak District

question_text: what is the highest mountain in the peak district

text: List of hills in the Peak District

text: This is a list of the hills of the Peak District of England.  Most lie within the Peak District National Park, but others lie outside its borders.  The list is sorted by absolute height, then by relative height.   Marilyns are marked in boldface. The top three are considered mountains as they are above 2,000 feet high.

text:
Peak

Absoluteheight (m)

Relativeheight

Grid reference

Kinder Scout

636

496.6

SK084875

Bleaklow

633

128

SK094960

Higher Shelf Stones

621

15

SK089948

Grindslow Knoll

601

15

SK110868

Black Hill

582

165

SE078046

Brown Knoll

569

36

SK083851

Shining Tor

559

236

SJ994737

Axe Edge Moor

551

84

SK035706

Lord's Seat

550

62

SK111834

Margery Hill

546

19

SK189956

Featherbed Moss

545

10

SE046011

Featherbed Top

544

c. 32

SK090920

Mill Hill

544

32

SK061904

Black Chew Head

542

35

SE056019

Back Tor

538

67

SK197909

Britland Edge Hill

523

c. 20

SE106027

Lost Lad

518

c. 10

SK193912

Mam Tor

517

62

SK127836

Oliver Hill

513

45

SK027675

Black Edge

507

99

SK062770

Shutlingsloe

506

134

SJ976695

The Roaches

505

c. 120

SK001638

Burbage Edge

500

25

SK029732

West Nab

500

c. 50

SK266940

Dead Edge End

499

c. 25

SE124017

South Head

494

c.44

SK060845

Merryton Low

489

c. 54

SK041610

Cats Tor

485

c.35

SJ995759

Slitherstone Hill

477

c.70

SK123819

Lose Hill

476

76

SK153854

Snailsden Pike End

475

c. 20

SE132034

Bradwell Moor

471

C 50

SK132801

Eldon Hill

470

c. 20

SK115811

Win Hill

462

c. 144

SK186850

High Neb

458

c. 103

SK227853

nr Ann Roach Farm

454

27

SK021655

Foxlow Edge

452

35

SK004756

Stanedge Pole

438

c. 24

SK247844

Higger Tor

434

c. 15

SK257819

Grin Low

430

c.45

SK054718

Eyam Moor - Sir William Hill

429

122

SK215778

Chrome Hill

c. 425

c. 45

SK070673

High Wheeldon

422

c. 25

SK100660

Snels Low

419

c. 25

SK113818

Shatton Edge (Abney Moor)

417

48

SK195807

Durham Edge (Abney Moor)

416

c. 40

SK180794

Black Hill (Whaley Bridge)

410

c. 105

SJ989821

Gautries Hill

410

c. 85

SK099810

Hen Cloud

410

60

SK008615

Burton Bole End

c. 410

c. 50

SK193809

Pike Low

405

11

SK180898

Croker Hill

402

98

SJ933677

Revidge

400

40

SK077599

Gradbach Hill

399

43

SK000653

Brittain's Plantation

398

c. 50

SK278930

Aleck Low

398

53

SK173595

Pilsbury Lodge

395

c. 40

SK121639

Totley Moor

395

c. 17

SK285788

Longstone Moor

391

c. 110

SK189733

Emlin

389

c. 10

SK240934

Houndkirk Hill

389

c. 10

SK284818

Wolfscote Hill

388

c. 100

SK136583

Gun

385

168

SJ970615

Rock Hall

383

16

SK227772

Crook Hill

382

c. 84

SK183872

Hawks Low

382

c. 35

SK170570

Pikenaze Hill

382

15

SE105004

Tegg's Nose

380

c. 30

SJ947725

Waggon Low

380

c. 16

SK116647

Harborough Rocks

379

65

SK243553

Minninglow Hill

372

c. 58

SK209573

Wetton Hill

372

c. 55

SK104563

Beeley Moor

371

84

SK293686

Eccles Pike

370

c. 132

SK035812

Wardlow Hay Cop

370

c. 47

SK179740

Slipper Low

368

c. 30

SK227569

Blakelow Hill

367

69

SK255594

Big Moor

367

19

SK260764

Hartcliff Hill

364

83

SE221018

Parkhouse Hill

c. 360

c. 35

SK079669

The Height

359

c. 30

SK250973

Middleton Moor

358

60

SK268556

Bole Hill

356

c. 50

SK184676

High Field

354

c. 50

SK162724

Abney Low

347

c. 45

SK202794

The Cloud

343

170

SJ904636

Heights of Abraham

338

c. 56

SK285587

Gibraltar Rocks

335

c. 25

SK249909

Blake Low

330

c. 28

SK220602

Low Moor

330

c. 10

SK183642

Bunster Hill

329

24

SK141516

Fin Cop

327

c. 90

SK175709

Stanton Moor

323

c. 108

SK245629

Bolehill

323

c. 105

SK294554

Wire Stone

318

c. 10

SK321634

Alport Height

314

c. 67

SK305515

Bole Hill

312

c. 15

SK290856

Ughill Height

311

c. 15

SK263907

Allman Well Hill

310

c. 25

SK281968

Nelson's Monument

310

c. 23

SK278731

Lees Moor

304

c. 142

SK249674

Hare Edge Hill

304

c. 16

SK303727

Thorpe Cloud

287

79

SK151510

Rainster Rocks

287

c. 10

SK220547

Calver Peak

285

20

SK229742

High Low

281

30

SK221802

Haven Hill

276

c. 15

SK212519

Wibben Hill

249

c. 10

SK184523

text: Mountains and hills of the Peak DistrictLists of mountains and hills of England

text: Articles with OS grid coordinatesIncomplete lists from August 2008